scholarly journals Discovery of Novel Recurrent Mutations and Clinically Meaningful Subgroups in Nodal Marginal Zone Lymphoma

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1669
Author(s):  
Jiwon Koh ◽  
Insoon Jang ◽  
Seongmin Choi ◽  
Sehui Kim ◽  
Ingeon Jang ◽  
...  
Keyword(s):  
B Cell ◽  
High Throughput Sequencing ◽  
Marginal Zone ◽  
Progression Free Survival ◽  
Cell Receptor ◽  
Marginal Zone Lymphoma ◽  
Ki 67 ◽  
Genetic Characteristics ◽  
Recurrent Mutations ◽  
Nodal Marginal Zone Lymphoma

Nodal marginal zone lymphoma (NMZL) is a rare B-cell neoplasm, the genetic and transcriptomic landscape of which are unclear. Using high-throughput sequencing for whole-exome and transcriptome, we investigated the genetic characteristics of NMZL in a discovery cohort (n = 8) and validated their features in an extended cohort (n = 30). Novel mutations in NFKBIE and ITPR2 were found in 7.9% (3/38) and 13.9% (5/36), respectively, suggesting roles for the NF-κB pathway and B-cell-receptor-mediated calcium signaling pathway in the pathogenesis of NMZL. RNA-seq showed that NMZLs were characterized by an aberrant marginal zone differentiation, associated with an altered IRF4-NOTCH2 axis and the enrichment of various oncogenic pathways. Based on gene expression profile, two subgroups were identified. Compared with subgroup 1, subgroup 2 showed the following: the significant enrichment of cell cycle-associated and MYC-signaling pathways, a more diverse repertoire of upstream regulators, and higher Ki-67 proliferation indices. We designated two subgroups according to Ki-67 labeling, and subgroup 2 was significantly associated with a shorter progression-free survival (p = 0.014), a greater proportion of large cells (p = 0.009), and higher MYC expression (p = 0.026). We suggest that NMZL has unique features and, in this study, we provide information as to the heterogeneity of this enigmatic entity.

scholarly journals Optimizing therapy for nodal marginal zone lymphoma

Blood ◽  
2016 ◽  
Vol 127 (17) ◽  
pp. 2064-2071 ◽  
Author(s):  
Catherine Thieblemont ◽  
Thierry Molina ◽  
Frédéric Davi
Keyword(s):  
B Cell ◽  
Marginal Zone ◽  
Immune Escape ◽  
B Cell Lymphoma ◽  
Cell Receptor ◽  
Marginal Zone Lymphoma ◽  
Gene Profiling ◽  
Biological Research ◽  
Number Of Patients ◽  
Nodal Marginal Zone Lymphoma

Abstract Nodal marginal zone lymphoma (NMZL) is a rare form of indolent small B-cell lymphoma which has only been clearly identified in the last 2 decades and which to date remains incurable. Progress in therapeutic management has been slow, largely due to the very small number of patients treated and the heterogeneity of treatments administered; thus, standard-of-care treatment is currently nonspecific for this lymphoma entity. In this review, treatments routinely used to manage adult NMZL patients are presented, principally based on immunochemotherapy (when treatment is needed). Biological research behind the key axes of agents currently under development is described; development of novel agents is heavily based on data from gene profiling and genome-wide sequencing research, uncovering a number of critical deregulated pathways specific to NMZL tumors. These include B-cell receptor, JAK/STAT, NF-κB, NOTCH, and Toll-like receptor signaling pathways, as well as intracellular processes such as the cell cycle, chromatin remodeling, and transcriptional regulation in terms of epigenetic modifiers, histones, or transcriptional co-repressors, along with immune escape via T-cell–mediated tumor surveillance. These pathways are examined in detail and a projection of how the field may evolve in the near future for an efficient personalized treatment approach for NMZL patients is presented.

scholarly journals Dramatic Response with Single-Agent Ibrutinib in Multiply Relapsed Marginal Zone Lymphoma with MYD88L265P Mutation

2017 ◽  
Vol 10 (3) ◽  
pp. 813-818 ◽  
Author(s):  
Ryan C. Lynch ◽  
Ranjana H. Advani
Keyword(s):  
B Cell ◽  
Signaling Pathway ◽  
Marginal Zone ◽  
Single Agent ◽  
Cell Receptor ◽  
Marginal Zone Lymphoma ◽  
B Cell Receptor ◽  
Receptor Signaling Pathway ◽  
B Cell Receptor Signaling ◽  
Cell Receptor Signaling

The B-cell receptor signaling pathway is important in the lymphomagenesis of many lymphomas, including marginal zone lymphoma (MZL). Herein we describe a case of extranodal MZL refractory to multiple lines of therapy. The presence of an IgM paraprotein prompted further evaluation, and the patient was found to have an MYD88L265P mutation. Treatment with ibrutinib led to a dramatic response with prompt resolution of symptoms and significant improvement in measurable sites of disease. The excellent response to ibrutinib in our patient with MYD88L265P-mutated refractory MZL supports a biological rationale for its use.

scholarly journals Improved biological insight and influence on management in indolent lymphoma. Talk 3: update on nodal and splenic marginal zone lymphoma

Hematology ◽  
2017 ◽  
Vol 2017 (1) ◽  
pp. 371-378 ◽  
Author(s):  
Catherine Thieblemont
Keyword(s):  
B Cell ◽  
Signaling Pathways ◽  
Marginal Zone ◽  
Cell Receptor ◽  
Nuclear Factor Κb ◽  
Therapeutic Strategies ◽  
Tumor Burden ◽  
Marginal Zone Lymphoma ◽  
Splenic Marginal Zone Lymphoma ◽  
B Cell Signaling

Abstract Splenic marginal zone lymphoma (SMZL) and nodal marginal zone lymphoma (NMZL) are rare indolent chronic B-cell lymphomas. Prognosis is typically good with median survival around 10-15 years. Management is generally based on the presence of symptoms or high tumor burden. There are no standard treatments for these 2 entities, and therapeutic strategies are rapidly evolving. Clinical developments for these 2 entities are oriented by genomic studies, with largely overlapping mutational profiles involving the NOTCH, B-cell receptor (BcR) and nuclear factor κB (NF-κB) signaling, chromatin remodeling, and the cytoskeleton. Although new therapeutic options based on targeting signaling pathways and overcoming resistance are increasingly available, few specific prospective studies are performed for these rare subtypes, limiting the conclusions that can be drawn. Novel drugs targeting B-cell signaling have shown promise, including ibrutinib and copanlisib. The second-generation oral immunomodalator (IMiD) lenalidomide showed impressive results when combined with rituximab. Other potential solutions include targeting the NF-κB, JAK/STAT, BCL2, NOTCH, and Toll-like receptor signaling pathways; however, studies in these 2 MZL entities are yet to prove a definitive benefit. Molecular profiling is now a cornerstone of diagnostic, prognostic, and therapeutic strategies to offer patient- and disease-specific solutions. The development of a wider range of effective targeted therapies and prognostic biomarkers is keenly awaited and is expected to strongly affect the natural history of SMZL and NMZL.

scholarly journals The genetics of nodal marginal zone lymphoma

Blood ◽  
2016 ◽  
Vol 128 (10) ◽  
pp. 1362-1373 ◽  
Author(s):  
Valeria Spina ◽  
Hossein Khiabanian ◽  
Monica Messina ◽  
Sara Monti ◽  
Luciano Cascione ◽  
...  
Keyword(s):  
B Cell ◽  
Marginal Zone ◽  
Marginal Zone Lymphoma ◽  
Key Points ◽  
Nodal Marginal Zone Lymphoma ◽  
Lymphoma Type

Key Points PTPRD lesions are among the most recurrent alterations in NMZL and appear to be enriched in this lymphoma type across mature B-cell tumors. NMZL and SMZL genetics overlap with the exceptions of PTPRD lesions, supporting their distinction as independent entities.

scholarly journals The B cell receptor in marginal zone lymphoma ontogeny and evolution

2020 ◽  
Vol 4 ◽  
pp. 10-10
Author(s):  
Laura Zaragoza-Infante ◽  
Andreas Agathangelidis ◽  
Maria Papaioannou ◽  
Anastasia Chatzidimitriou ◽  
Kostas Stamatopoulos
Keyword(s):  
B Cell ◽  
Marginal Zone ◽  
Cell Receptor ◽  
Marginal Zone Lymphoma ◽  
B Cell Receptor

scholarly journals IGHV mutational status of nodal marginal zone lymphoma by NGS reveals distinct pathogenic pathways with different prognostic implications

2019 ◽  
Vol 477 (1) ◽  
pp. 143-150 ◽  
Author(s):  
Massimo Granai ◽  
Teresa Amato ◽  
Arianna Di Napoli ◽  
Raffaella Santi ◽  
Federica Vergoni ◽  
...  
Keyword(s):  
B Cell ◽  
Heavy Chain ◽  
Marginal Zone ◽  
Germ Line ◽  
Direct Sequencing ◽  
Variable Region ◽  
Marginal Zone Lymphoma ◽  
Cell Of Origin ◽  
Mutational Status ◽  
Nodal Marginal Zone Lymphoma

AbstractThe precise B cell of origin and molecular pathogenesis of nodal marginal zone lymphoma (NMZL) remain poorly defined. To date, due to the rarity of NMZL, the vast majority of already-published studies have been conducted on a limited number of samples and the technical approach to analyze the immunoglobulin genes was of amplifying rearranged variable region genes with the classical direct sequencing of the PCR products followed by cloning. Here, we studied the B cell Ig heavy-chain repertoires by next-generation sequencing (NGS) in 30 NMZL cases. Most of the cases were mutated (20/28; 71.5%) with homologies to the respective germ line genes ranging from 85 to 97, 83%, whereas 8/28 (28.5%) were unmutated. In addition, our results show that NMZL cases have a biased usage of specific immunoglobulin heavy-chain variable (IGHV) region genes. Moreover, we documented intraclonal diversity in all (100%) of the mutated cases and ongoing somatic hypermutations (SHM) have been confirmed by hundreds of reads. We analyzed the mutational pattern to detect and quantify antigen selection pressure and we found a positive selection in 4 cases, whereas in the remaining cases there was an unspecific stimulation. Finally, the disease-specific survival and the progression-free survival were significantly different between cases with mutated and unmutated IGHV genes, pointing out mutational status as a possible new biomarker in NMZL.

scholarly journals Stereotyped patterns of B-cell receptor in splenic marginal zone lymphoma

Haematologica ◽  
2010 ◽  
Vol 95 (10) ◽  
pp. 1792-1796 ◽  
Author(s):  
S. Zibellini ◽  
D. Capello ◽  
F. Forconi ◽  
P. Marcatili ◽  
D. Rossi ◽  
...  
Keyword(s):  
B Cell ◽  
Marginal Zone ◽  
Cell Receptor ◽  
Marginal Zone Lymphoma ◽  
B Cell Receptor ◽  
Splenic Marginal Zone Lymphoma

Nodal marginal zone lymphoma: gene expression and miRNA profiling identify diagnostic markers and potential therapeutic targets

Blood ◽  
2012 ◽  
Vol 119 (3) ◽  
pp. e9-e21 ◽  
Author(s):  
Alberto J. Arribas ◽  
Yolanda Campos-Martín ◽  
Cristina Gómez-Abad ◽  
Patrocinio Algara ◽  
Margarita Sánchez-Beato ◽  
...  
Keyword(s):  
Gene Expression ◽  
B Cell ◽  
Marginal Zone ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Marginal Zone Lymphoma ◽  
Survival Pathways ◽  
Gene Sets ◽  
Nodal Marginal Zone Lymphoma ◽  
Follicular Lymphomas

Abstract Nodal marginal zone lymphoma (NMZL) is a small B-cell neoplasm whose molecular pathogenesis is still essentially unknown and whose differentiation from other small B-cell lymphomas is hampered by the lack of specific markers. We have analyzed gene expression, miRNA profile, and copy number data from 15 NMZL cases. For comparison, 16 follicular lymphomas (FLs), 9 extranodal marginal zone lymphomas, and 8 reactive lymph nodes and B-cell subtypes were included. The results were validated by quantitative RT-PCR in an independent series, including 61 paraffin-embedded NMZLs. NMZL signature showed an enriched expression of gene sets identifying interleukins, integrins, CD40, PI3K, NF-κB, and TGF-β, and included genes expressed by normal marginal zone cells and memory B cells. The most highly overexpressed genes were SYK, TACI, CD74, CD82, and CDC42EP5. Genes linked to G2/M and germinal center were down-regulated. Comparison of the gene expression profiles of NMZL and FL showed enriched expression of CHIT1, TGFB1, and TACI in NMZL, and BCL6, LMO2, and CD10 in FL. NMZL displayed increased expression of miR-221, miR-223, and let-7f, whereas FL strongly expressed miR-494. Our study identifies new candidate diagnostic molecules for NMZL and reveals survival pathways activated in NMZL.

Splenic marginal zone lymphoma: proposal of new diagnostic and prognostic markers identified after tissue and cDNA microarray analysis

Blood ◽  
2005 ◽  
Vol 106 (5) ◽  
pp. 1831-1838 ◽  
Author(s):  
Elena Ruiz-Ballesteros ◽  
Manuela Mollejo ◽  
Antonia Rodriguez ◽  
Francisca I. Camacho ◽  
Patrocinio Algara ◽  
...  
Keyword(s):  
B Cell ◽  
Cdna Microarray ◽  
Marginal Zone ◽  
Prognostic Markers ◽  
Variable Region ◽  
Cell Receptor ◽  
Marginal Zone Lymphoma ◽  
Molecular Entity ◽  
Splenic Marginal Zone Lymphoma ◽  
Mutational Status

Abstract Splenic marginal zone lymphoma (SMZL) is a newly recognized lymphoma type whose precise molecular pathogenesis is still essentially unknown. This hampers differential diagnosis with other small B-cell malignancies. With the aim of characterizing this tumor more comprehensively, and of identifying new diagnostic and prognostic markers, we performed cDNA microarray expression profiling and tissue microarray (TMA) immunohistochemical studies in a relatively large series of 44 SMZLs. The results were related to immunoglobulin heavy chain variable region (IgVH) mutational status and clinical outcome. SMZLs display a largely homogenous signature, implying the existence of a single molecular entity. Of the genes deregulated in SMZLs, special mention may be made of the genes involved in B-cell receptor (BCR) signaling, tumor necrosis factor (TNF) signaling and nuclear factor-κB (NF-κB) activation, such as SYK, BTK, BIRC3, TRAF3, and LTB. Other genes observed were SELL and LPXN, which were highly expressed in spleen, and lymphoma oncogenes, such as ARHH and TCL1. In contrast, the genes CAV1, CAV2, and GNG11 located in 7q31, a commonly deleted area, were down-regulated in the entire series. A comparison with the genes comprising the signature of other small B-cell lymphomas identified 3 genes whose expression distinguishes SMZL, namely ILF1, SENATAXIN, and CD40. Shorter survival was associated with CD38 expression, naive IgVH genes, and the expression of a set of NF-κB pathway genes, including TRAF5, REL, and PKCA. (Blood. 2005;106:1831-1838)

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